Mumps virus causes acute infections in humans and about 10% of infection leads to aseptic meningitis. Although several mumps virus genome sequences are known, molecular bases of mumps virus pathogenesis are not clear. Long-term goal of this proposal is to understand how virus overcomes host defense mechanisms, especially how viral proteins overcome host innate immunity at molecular levels in tissue culture cells as well as in animals. The small hydrophobic protein (SH) of simian virus 5 (SV5), a virus closely related to mumps virus, plays an important role in inhibiting tumor necrosis factor (TNF)-alpha activated apoptotic pathway and the deletion of SH results in an attenuated virus in vivo. It is hypothesized that inhibition of apoptosis by virus-infected cells contributes to viral pathogenesis and mumps virus small hydrophobic protein (SH) plays essential roles in inhibition of cell death in virus-infected cells like SH of SV5 even though both SH proteins have no sequence homologies. To test these hypothesis, (1) a reverse genetics system in which infectious mumps virus from cDNA of a clinical isolate will be obtained will be established, (2) mumps virus lacking SH gene (rMuVdeltaSH) will be generated and (3) compared with its parental mumps virus in tissue culture cells and in a rat model system. Since my joining Penn State University in 2001 as a tenure-track assistant professor of virology, we have identified pathways leading to apoptosis in SV5 lacking SH (rSV5deltaSH) or in SV5 lacking the conserved C-terminus of V (rSVSVdeltaC)- infected cells. I hope to establish a research program in understanding the relationship between pathogenicity of mumps virus and functions of individual mumps virus proteins. The proposed work in this application builds on our current work on paramyxovirus SV5 SH function, expands our current work from SV5 SH to mumps virus SH and redirects our focus on functions of viral proteins in tissue culture system to that in an animal model system as well as in tissue culture cells.